SGCD

Inheritance Pattern: AR

Disease ID:MONDO:0011028

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: ClinGen

SGCD was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 1996 (Nigro et al., PMID: 8841194). At least eight variants (e.g. missense, nonsense, frameshift, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least eleven probands in seven publications (PMIDs: 8841194, 19259135, 20623375, 10838250, 10735275, 9832045, 30733730). Variants in this gene segregated with the disease in eight additional family members and many other heterozygous carriers. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is protein loss of function, with the loss or disruption of δ-sarcoglycan causing disruption and mislocalization of the sarcoglycan complex which causes destabilization of the sarcolemma and the resulting muscular phenotypes (PMID: 26709803). Of note, this gene has also been implicated in dilated cardiomyopathy which has been assessed separately.This gene-disease association is supported by two KO mouse models, expression studies, a partial mouse rescue, and intercellular protein interactions. The KO mouse models provide strong evidence by recapitulating the observed phenotypes in humans and a partial rescue in one was performed via restoring some of the wildtype SGCD functionality via embryonic stem cells. Expression evidence clearly links the protein to skeletal and cardiac muscle where phenotypes are observed. Finally, the protein physically interacts with all the other sarcoglycans which are all associated with AR LGMD when their function is affected. In summary, SGCD is definitively associated with autosomal recessive limb-girdle muscular dystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on April 10, 2020 (SOP Version 7). This gene curation was re-approved and published on 11/14/24 by the Muscular Dystrophies and Myopathies GCEP to reflect the change in the panel's name from LGMD GCEP to MDM GCEP. As part of this process, the genetic evidence was re-scored in accordance with SOP version 11.

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0011028

Submitter: Myriad Women's Health

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0011028

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011702

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0011702

Submitter: ClinGen

SGCD was originally evaluated for DCM by the ClinGen DCM GCEP on 22 November 2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 30th March 2025. At the time of recuration there are minimal changes in score and new evidence; Therefore, the clinical validity classification did not change and remains Limited. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. SGCD was first reported in relation to autosomal dominant dilated cardiomyopathy in 2000 (Tsubata et al, PMID 10974018). Human genetic evidence supporting this gene-disease relationship includes case-level data. At least 30 variants (20 missense, one splice, one nonsense, two frameshift, three deletion and three intronic polymorphisms) have been reported in humans. Though most of these variants are found too commonly to explain disease. Variants in this gene have been reported in at least 33 probands in 11 publications (Tsubata et al, 2000, PMID: 10974018; Karkkainen et al, 2003, PMID: 14564412; Sylvius et al, 2003, PMID: 12794684; Baydar et al, 2016, PMID: 27488758; Bauer et al, 2009, PMID: 19259135; Chen et al, 2015, PMID: 26720722; Hata et al, 2019, PMID: 31024045, Alimohamed et al, 2023, PMID: 36270459, Shen C. et al. 2022, PMID: 35284542, Escobar-Lopez L. et al. 2021, PMID 34674813, Pugh TJ, et al. 2014, PMID: 24503780). A variant (S151A) in this gene segregated with disease in 2 additional family members. However, the S151A variant occurs too frequently to explain disease and alternative genetic causes of disease in the family were not ruled out. This gene-disease relationship has been studied in at least one case-control study (Mazzarotto et al, 2020, PMID: 31983221) at the aggregate variant level. There was no enrichment of SGCD found in the DCM cohort compared to controls (p=0.74). In addition, this gene-disease association is supported by multiple animal models (pig, hamster, mouse and drosophila), expression studies, and rescue studies in two mouse models. SGCD has also been implicated in autosomal recessive Limb Girdle Muscular Dystrophy (LGMD) which has been assessed separately (definitive, November 14, 2024). Although this gene-disease assertion is supported by experimental evidence, there is not convincing evidence directly implicating this gene in humans. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of SGCD and AD DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 30th March 2025 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0011028

Submitter: Orphanet